Sustained-release pharmaceutical preparations are developed for the purpose of improving compliance as a result of reducing the number of times they are administered or preventing adverse reaction by making the blood concentration fluctuations (peak/trough) smaller and thereby realizing stable therapeutic results, and various pharmaceutical preparations have been developed in recent years. Various sustained-release pharmaceutical preparations have been created by the present applicant as well. Of these, hydrogel sustained-release pharmaceutical preparations comprising a hydrophilic base (also gelation enhancer hereafter) and hydrogel-forming polymer can be easily manufactured because the composition and components are simple. This sustained-release pharmaceutical preparation can release a drug in the upper digestive tract, including the stomach and the small intestine, as well as the lower digestive tract, including the colon. In other words, the entire digestive tract can be used as the site of absorption. Therefore, it is highly practical and very useful as a pharmaceutical preparation with small inter-subject variation in terms of drug absorption in humans (for instance, refer to Patent Reference 1: International Publication Pamphlet No. 94/06414).
The inventors of inventions relating to the above-mentioned sustained-release pharmaceutical preparations proposed various polymers as hydrogel-forming polymers, but of these, polyethylene oxide is capable of imparting particularly good controlled-release performance to the pharmaceutical preparation and therefore, polyethylene oxide is usually selected as the polymer of first choice for the hydrogel-forming polymer. However, polyethylene oxide is a water-soluble thermoplastic resin in the form of a white powder or granules whose molecular weight reaches several 100,000 to several 1,000,000 that is obtained by polymerization of ethylene oxide, and polyethylene oxide with a molecular weight of 2,000,000 or higher becomes very sticky when exposed to moisture. Therefore, when water is added to polyethylene oxide or polyethylene oxide is handled under high humidity, it shows a very high viscosity, and polyethylene oxide can therefore be perceived as a substance that is difficult to handle during each process of pulverization, granulation, tableting, and the like, particularly during granulation. Therefore, methods have been presented in the past, including wet granulation, whereby for example, a chloride solvent such as dichloromethane or carbon tetrachloride or an alcohol solvent such as methanol, ethanol, or propanol is used alone or as a mixture with water direct tableting, and dry granulation when sustained-release pharmaceutical preparations that use polyethylene oxide, particularly matrix-type controlled-release pharmaceutical preparations that contain polyethylene oxide as the controlled-release base, contain a high concentration of polyethylene oxide with a high viscosity, (for instance, refer to Patent Reference 1: International Publication Pamphlet No. 94/06414, Patent Reference 2: International Publication Pamphlet No. 01/10466, Patent Reference 3: Specification of U.S. Pat. No. 5,273,758).
In addition, there is also a method of producing a pharmaceutical preparation by spray granulation of tablet starting materials comprising polyethylene oxide with a molecular weight of 100,000 using an aqueous hydroxypropylmethyl cellulose solution (Patent Reference 4: Specification of U.S. Pat. No. 4,662,880, Patent Reference 5: Specification of U.S. Pat. No. 4,810,502 (corresponds to Japanese Kokai Patent No. Hei 7-215869)). Although the conditions of wet granulation, and the like, are not entered to such an extent that granulation can be conducted by persons in the field, polyethylene oxide with a molecular weight of 2,000,000 or higher has a viscosity of 2,000 mPa·s or higher (millipascal second: aqueous 2% w/v solution, 25° C.) and this viscosity is dramatically higher than the viscosity of polyethylene oxide with a molecular weight of 100,000 of 30 to 50 mPa·s (aqueous 5% w/v solution, 25° C.). Therefore, it appears that when the same wet granulation method is used, granulation proceeds too far or a powder the particles of which become thread-like in appearance is produced and a powder that is appropriate for tableting cannot be made in that powder particles with poor fluidity are produced, and the like.
Furthermore, it goes without saying that when a controlled-release pharmaceutical preparation containing a low dose of drug is made, it must be made so that the active ingredient is contained uniformly per unit of the pharmaceutical preparation. Nevertheless, there are also problems with direct tableting and dry granulation in that the drug is scattered and the drug content is reduced, or uniformity of drug content is diminished, and further, productivity is poor because the granulation/pulverization process is repeated, and the like.
Furthermore, a variety of problems are indicated with wet granulation using an organic solvent, including environmental pollution, safety during manufacture (risk of explosion, and the like), expenditure on manufacturing facilities (explosion-proof equipment, use of organic solvents, and recovery facilities), and the like (for instance, refer to Patent Reference 3).
Patent Reference 1:
International Publication Pamphlet No. 94/06414
Patent Reference 2:
International Publication Pamphlet No. 01/10466
Patent Reference 3:
Specification of U.S. Pat. No. 5,273,758
Patent Reference 4:
Specification of U.S. Pat. No. 4,662,880
Patent Reference 5:
Specification of U.S. Pat. No. 4,810,502 (corresponds to Japanese Kokai Patent No. Hei 7[1995]-215869)
Consequently, there is the need today for the presentation of a powder that is appropriate for tableting in order to manufacture a pharmaceutical composition for controlled release of active substances containing polyethylene oxide with a molecular weight of 2,000,000 or higher and having good uniformity of drug content, the presentation of a controlled-release pharmaceutical composition containing this powder, and the presentation of a method of manufacturing this powder or a controlled-release pharmaceutical composition containing this powder.